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Abstract:

The invention relates to the simplified treatment of mastitis with
enrofloxacin or ciprofloxacin, in particular in the case of cows.

Claims:

1. Method for treating mastitis in an animal in which enrofloxacin is
administered intravenously twice, once a day on two consecutive days, to
the animal in need thereof

2. The method of claim 1, wherein enrofloxacin is administered at a rate
of 2.5 to 7 mg/kg of body weight of the animal

3. The method of claim 1, wherein the concentration of enrofloxacin
administered to the animal is from 1 to 10% by weight.

4. The method of claim 1, wherein the animal is selected from the group
consisting of a sheep, a goat, and a cow.

Description:

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. Ser. No. 11/718,999,
which is a 35 U.S.C. §371 National Stage Application of
International Application No. PCT/EP2005/011553, filed Oct. 28, 2005, the
entire contents of which are incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention relates to the simplified treatment of mastitis with
enrofloxacin or ciprofloxacin, in particular in the case of cows.

BACKGROUND OF THE INVENTION

[0003] The active compound enrofloxacin has been successfully employed for
years in many countries for treating bacterially determined infectious
diseases in animals (Baytril®). While the classical areas of use
primarily comprise respiratory and enteric diseases, skin infections,
urinary tract infections, teat infections and joint infections are also
successfully treated. The customary treatment scheme in this connection
envisages repeated administration over a period of from three to five
days. Attempts to shorten the period of treatment while retaining the
size of the dose have led in the past to the loss of the sought-after
therapeutic efficacy.

[0004] U.S. Pat. No. 5,756,506 relates to the treatment of infections with
a single administration of fluoroquinolones, such as enrofloxacin;
however, this treatment uses a markedly higher dose.

SUMMARY OF THE INVENTION

[0005] It has now been found, surprisingly, that parenterally administered
enrofloxacin has an unexpectedly good effect in the treatment of mastites
(udder inflammations), such that the number of administrations can be
reduced and the treatment thereby simplified.

[0006] The invention therefore relates to the use of enrofloxacin for
producing pharmaceuticals for the parenteral treatment of bacterially
determined mastites with at most two administrations.

[0007] The invention furthermore relates to a method for treating
bacterially determined mastites, in which method enrofloxacin is
parenterally administered at most twice to the animal in question.

[0008] Without this thereby limiting the invention, this surprising
finding can be explained by the following investigative results:

[0009] it was already known from serum kinetics investigations that,
following administration, a small proportion of the enrofloxacin is
metabolized to ciprofloxacin. However, the effect of the enrofloxacin is
normally also in fact essentially to be attributed to this molecule and
not to its metabolite ciprofloxacin. In connection with investigating the
substances having an antibacterial effect in bovine milk following the
parenteral administration of enrofloxacin, we discovered a high
antibacterial activity (enrichment of active compounds as compared with
the serum concentration) in association with a surprisingly high
proportion of ciprofloxacin (of the order of size of 90%) and a
surprisingly low proportion of enrofloxacin (of the order of size of 10%)
in the milk; this is roughly a reversal of the ratio that was expected.
In-vitro activity comparisons show that, in the case of bacterial species
which play an important role as pathogens in mastites, ciprofloxacin has
a markedly more powerful effect than enrofloxacin.

[0010] According to another embodiment, the invention therefore relates to
the use of ciprofloxacin for producing pharmaceuticals for treating
mastitis.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] Enrofloxacin is a fluoroquinolonecarboxylic acid having the
systematic designation
1-cyclopropyl-7-(4-ethyl-1-piperazinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quin-
olone-carboxylic acid:

[0013] The active compounds can be used in the form of their
pharmaceutically acceptable salts, specifically in the form of salts with
inorganic acids, such as hydrochloric acid, hydrobromic acid, hydroiodic
acid, sulphuric acid or phosphoric acid, or organic acids, such as formic
acid, acetic acid, propionic acid, lactic acid, maleic acid, fumaric
acid, citric acid, ascorbic acid, succinic acid, glutaric acid and
tartaric acid, polyhydroxycarboxylic acids, such as gluconic acid,
galacturonic acid and glucuronic acid, amino acids, such as glutamic acid
and aspartic acid, and sulphonic acids, such as methanesulphonic acid and
ethanesulphonic acid. Suitable bases for forming salts are, for example,
inorganic bases, such as NaOH, KOH, Ca(OH)2 and ammonia, and organic
bases, such as amines, e.g. mono , di and trialkylamines, substituted
amines, such as ethanolamine, cyclic amines, such as morpholine or
piperazine, basic amino acids, such as arginine, lysine and codeine, or
N-methylglucamine. The active compounds and their preparation are
described, for example, in U.S. Pat. No. 4,670,444.

[0014] Preparations for the parenteral administration are likewise known
in principle, see, for example, U.S. Pat. No. 4,772,605 and U.S. Pat. No.
5,998,418, which publications are hereby expressly incorporated by
reference.

[0015] Emulsions, suspensions and, in particular, solutions are suitable
for the parenteral administration.

[0016] The preferred solvent is water, which can, where appropriate, also
be used in a mixture with other solvents. These other solvents include:
alcohols such as monohydric or polyhydric primary or secondary or
tertiary alcohols (e.g. ethanol, butanol, benzyl alcohol, glycol,
propylene glycol, triethylene glycol, polyethylene glycol, glycerol and
propylene glycol) as well as N-methylpyrrolidone.

[0017] However, it is also possible to conceive of oil-based preparations;
these are usually suspensions. In the preparations according to the
invention, the active compounds are generally present at concentrations
of from 0.1 to 30% by weight, preferably from 0.5 to 20% by weight,
particularly preferably from 1 to 10% by weight.

[0018] The use of highly pure quinolonecarboxylic acids for preparing
parenterally administrable solutions is described in EP A 287 926; this
document is hereby expressly incorporated by reference.

[0019] Acidic formulations can be used; preferred pH values are in the
range from pH 3 to 6.5, particularly preferably from 3 to 5. The acids
employed can in principle be those which are mentioned above for forming
salts; preferred examples are lactic acid and gluconolactone. Solutions
of the lactic acid salts of quinolonecarboxylic acids, in particular
ciprofloxacin, which are suitable for injection purposes are described in
EP A 138 018; other acidic infusion solutions of ciprofloxacin are
disclosed in EPA 219 784; acidic injection solutions for enrofloxacin are
described in U.S. Pat. No. 5,998,418; these three documents are hereby
expressly incorporated by reference.

[0020] Preference is given to basic formulations which contain
superequimolar quantities of bases; these preparations have a pH of from
8 to 12.5, preferably from 9 to 12, particularly preferably from 9.5 to
11.5. Suitable bases are, for example, those mentioned above in
connection with the salts, preferably the alkali metal hydroxides such as
NaOH and, in particular, KOH. A base which is also particularly preferred
is arginine. These formulations are, for example, described in more
detail in U.S. Pat. No. 4,772,605; this document is hereby expressly
incorporated by reference.

[0021] The pharmaceutical preparations can also comprise customary
auxiliary substances; these are nontoxic pharmaceutical substances such
as diluents, thickeners, absorption accelerators, absorption inhibitors,
crystal growth inhibitors, complexing agents, light-stability agents,
antioxidants and preservatives. The following may be mentioned by way of
example: as thickeners, methyl cellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, sodium carboxymethyl cellulose,
polyvinylpyrrolidone and gelatine; as preservatives, p-hydroxybenzoic
acid esters, phenols, chlorobutanol, benzyl alcohol, ethanol, butanol,
1,3-butanediol, chlorohexidine salts, benzoic acid and salts, and sorbic
acid; as antioxidants, ascorbic acid, L-cystein, thiodipropionic acid,
thiolactic acid, monothioglycerol, propyl gallate, sodium metadisulphite
or sodium sulphite; as complexing agents, sodium salts of
ethylenediaminetetraacetic acid, phosphates, acetates and citrates; as a
crystal growth inhibitor, polyvinylpyrrolidone. Local anaesthetics, such
as procaine hydrochloride or lidocaine hydrochloride, can be added where
appropriate. The concentration of the auxiliary substances which may
possibly be employed varies greatly and, in customary formulations, can
be in the range of from 0.1 to 30% by weight for the total quantity of
auxiliary substances present.

[0022] Sodium chloride, glucose, fructose, glycerol, sorbitol, mannitol,
sucrose, xylitol, or mixtures of these substances, can, for example, be
added in a quantity which is suitable for establishing isotonic
conditions.

[0023] In principle, bacterially determined, in particular coliform,
mastites can, in accordance with the invention, be treated in all
mammals. However, the treatment of milk-yielding productive animals is of
particular importance; preferred examples which may be mentioned are:
sheep, goats and, in particular, cows. The following pathogens may, in
particular, be mentioned in this connection: E. coli, Klebsiella spp.,
Enterobacter spp., Salmonella spp., Citrobacter spp., Serratia spp.,
Shigella spp., Edwardsiella spp., Hafnia spp., Morganella spp.,
Providencia spp., Yersinia spp., Staphylococcus aureus, Staphylococcus
spp., Pseudomonas spp., Mycoplasma spp. and Erwinia spp., and the
following infections of the mammary gland which are caused by noncoliform
bacteria.

[0024] Administration is effected parenterally, usually by means of
injection, for example intramuscularly, preferably intravenously or
subcutaneously.

[0025] In the treatment, from 1 to 10 mg, preferably from 2 to 8 mg,
particularly preferably from 2.5 to 7 mg, of the active compound per kg
of body weight are usually administered per day. The administration is
preferably effected on two consecutive days. Only one administration is
normally required per day.

[0026] In addition, frequently occurring mixed and monoinfections, or
mixed infections with, for example, E. coli and staphylococcus or
mycoplasma are treated satisfactorily.

EXAMPLES

Formulation Examples

[0027] The formulations of the following examples can be employed in
accordance with the invention. Their preparation is disclosed in the
prior art:

[0040] In a clinical study, the efficacy of enrofloxacin (Baytril® 10%
injection solution, commercial product) in the treatment of mastitis was
compared with that of a cefquinome-based commercial product (Cobactan
LC®) which is customarily used for treating mastitis. Enrofloxacin
was administered intravenously in a dose of 5 mg/kg of body weight once
daily on two consecutive days. Cefquinome was administered, by
intramammary administration into the infected udder quarter, at a dose of
75 mg every 12 hours after three consecutive milkings.

[0041] Result:

[0042] Taken overall, the enrofloxacin group was in better condition after
the treatment than was the group which was treated with the comparison
product.

[0043] The treatment with enrofloxacin was well tolerated by all the cows.

[0044] The study showed that, with the administration as stated, the
enrofloxacin product is suitable for treating acute coliform mastitis in
dairy cows. When the general and local symptoms, the milking performance
and the bacteriological results were assessed, enrofloxacin was found to
be superior to the comparison product.